Oral Acyclovir To Suppress Frequently Recurrent Herpes Labialis: A Double-Blind, Placebo-Controlled Trial

Methods

Study Sample

Patients were enrolled at the outpatient facilities of the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Bethesda, Maryland, from February 1988 to March 1990. Otherwise healthy adults, ages 18 to 50, who reported histories of 6 or more episodes of herpes labialis per year were eligible for entry into the study. Patients with child-bearing potential were required to practice effective methods of birth control, and women were required to have a negative pregnancy test.

Study Design

At the initial clinic visit informed consent was obtained, a history and physical examination were done, and blood and urine samples were obtained for routine hematology, blood chemistry tests, urinalysis, and urine pregnancy testing as well as for HSV serology testing. Patients then began a 4-month observation period to document the frequency of recurrent herpes labialis because it was felt that only in patients with frequent recurrences would treatment with daily oral acyclovir be justified.

Those patients who had two or more recurrences (at least one of which was confirmed by culture) during the observation period were randomized to receive either acyclovir, 400 mg twice daily, or matched placebo (provided by Burroughs Wellcome Company, Research Triangle Park, North Carolina) for 4 months (treatment course A) and then switched to the opposite therapy for another 4 months (treatment course B). Study medication was then discontinued, and patients were followed to first recurrence of herpes labialis.

During all study phases patients were seen in clinic at monthly intervals and were questioned regarding signs or symptoms of recurrent disease and medication compliance. Urine pregnancy testing was done monthly for women of child-bearing potential, and routine hematologic and blood chemistry testing was done on all patients at 4-month intervals. In addition, patients were instructed to return to clinic within 24 hours of the onset of an outbreak of herpes labialis. Recurrent disease was documented by physical examination, viral culture, and photography. Patients were also instructed to keep home records in which they documented the onset, duration, and location of all outbreaks and noted any missed medication.

Viral Studies

Specimens obtained by aspiration or swabbing of suspected lesions were transported in veal infusion broth on ice to the laboratory. Roller tubes containing human diploid fibroblasts or rabbit kidney cells, or both were inoculated in duplicate with 0.2 mL of the lesion material and were observed for 14 days for cytopathic effects indicative of HSV infection. Positive cultures were typed using fluorescein-labeled monoclonal antibodies specific for HSV-1 or HSV-2 (Syva Microtrak, Syva Company, Palo Alto, California). Antiviral sensitivity analysis was carried out on selected isolates using a radiolabeled probe to quantify viral DNA (Hybriwix HSV Antiviral Susceptibility Test Kit, Diagnostic Hybrids, Inc., Athens, Ohio).

Study Definitions

Documentation of a recurrence was determined by clinical examination and viral culture of suspected lesions. Clinical documentation was based on observation of crusts, vesicles, or grouped lesions in any stage, occurring in an anatomic area appropriate for recurrent herpes labialis. Any suspected lesion whose viral culture was scored as positive was considered virologically documented. The duration of a recurrence was defined as the time to complete healing.

Statistical Methods

In keeping with the crossover design of the study, paired analyses were used to assess the efficacy of treatment. Thus, a paired-sample t-test was applied to the respective differences between the number of recurrences on placebo and the number on acyclovir; also, a sign test [14] was applied to the corresponding proportions of episodes with virus culture-positive lesions. A McNemar test [14] was used to compare the number of patients who had a recurrence on placebo but not on acyclovir with the number who had a recurrence on acyclovir but not placebo. Analysis of the time to first recurrence on each treatment was complicated by two features of these data: censoring at the end of the treatment period (about 120 days) and the unexplained finding that virologically determined recurrence times on placebo were significantly longer among patients in course B than among patients in course A. The first feature introduced doubly censored within-patient treatment differences that led to the use of a modified Gehan test [15] applied to between course differences classified according to identity of the first course treatment. The second feature required that virologically determined course B recurrence times be eliminated; an ordinary Gehan test [16] was applied to the course A virologically determined recurrence times for acyclovir and placebo recipients. Analysis of duration of recurrences on acyclovir compared with placebo treatment was made using a paired-sample t-test.

Carryover effects were obviated by excluding from data analysis recurrences observed during the first week of each of the four study periods, as stipulated by the study protocol.

Results

Fifty-six patients entered into the pretreatment observation phase of this study. Twenty-two patients had two or more recurrences of herpes labialis and were randomized into two groups to receive study medication. The demographic and clinical characteristics of these groups are shown in Table 1. Patients in the first group received acyclovir for treatment course A and placebo for treatment course B, whereas patients in the second group received these medications in the reverse order. Two patients from the first group dropped out of the study, one because of headache and nausea after receiving five doses of acyclovir in treatment course A and one for administrative reasons after successfully completing the course of acyclovir. These patients were excluded from final analysis. An additional patient from the first group had nausea, vomiting, and diarrhea, attributed to gastroenteritis, during month 2 of acyclovir therapy on treatment course A, and study medication was discontinued for 1 day. When therapy was resumed, no adverse effects were noted, and the data from this patient were included in the final evaluation. Study medication was otherwise well tolerated by all patients. According to patient home records, 99% of prescribed study medication was taken during both acyclovir and placebo treatments.

Effect of Therapy

Twenty patients completed treatment with both acyclovir and placebo, and the paired analysis of the data from these patients was used to evaluate treatment effect. Treatment with acyclovir resulted in a greater than 2.5-fold prolongation in the median time to first clinically determined recurrence (46 to 118 days, P = 0.05) and time to first virologically determined recurrence (46 to > 118 days, P = 0.002) (Table 2).

Acyclovir therapy also resulted in a 53% reduction in the mean number of clinically documented recurrences per 4-month period of treatment (1.80 to 0.85 episodes per patient, P = 0.009) and a 71% reduction in the mean number of culture-positive recurrences (1.40 to 0.40 episodes per patient, P = 0.003) (Table 2). Seventeen patients had a total of 36 clinically confirmed recurrences of herpes labialis while on placebo treatment, whereas 10 patients on acyclovir therapy had a total of 17 recurrences (P = 0.03 for comparison of patients having recurrence on placebo but not acyclovir [n = 9] compared with those having recurrence on acyclovir but not placebo [n = 1]). Sixteen patients on placebo had virologically confirmed recurrences, whereas only six did on acyclovir (P < 0.01 for comparison of patients experiencing recurrence on placebo but not acyclovir [n = 11] compared with those with recurrence on acyclovir but not on placebo [n = 1]). Although not designed to do so optimally, this study permitted some assessment of the duration of lesions based on patient home records. There was an apparent reduction in the mean (± SE) duration of lesions to 4.3 ± 0.9 days during acyclovir therapy compared with 7.9 ± 1.6 days for recurrences that developed while on placebo (P = 0.11; 95% CI interval for the difference, 7.89 −4.27 = 3.62, is −1.02,8.26). When therapy was discontinued, the times to first clinically documented and to first virologically documented recurrences (median, 28 days for both) were similar to those times observed for placebo treatment during the study, indicating no prolonged effect of treatment.

Viral Studies

Clinical recurrences were confirmed by viral culture for 28 of 36 (78%) recurrences in placebo courses and for 8 of 17 (47%) recurrences in acyclovir courses (P = 0.04). Initial isolates from 21 of 22 patients were determined by monoclonal antibody analysis to be HSV-1, whereas the isolate of the remaining patient, who subsequently withdrew from the study, was determined to be HSV-2. Antiviral sensitivity analysis was completed on 18 pretreatment isolates (18 patients), 24 treatment isolates (18 patients), and 13 post-treatment isolates (13 patients). This analysis included at least one isolate from each patient in the study and included treatment and post-treatment isolates from all six patients who had a recurrence on acyclovir in this study. All isolates were sensitive to acyclovir (inhibiting dose₅₀ ≤ 1.0 µg/mL).

Discussion

The results of this study show that twice-daily oral acyclovir treatment effectively reduces the risk for recurrent herpes labialis in otherwise healthy patients who have frequently recurrent disease. Patients enrolled in this study had a 53% reduction in the mean number of recurrences while on acyclovir therapy compared with placebo. Moreover, recurrences developing on acyclovir were less likely to be culture positive, and the records that patients kept suggest that the time to healing of those recurrences was reduced.

Previous studies have established the efficacy of acyclovir in the treatment and suppression of oral HSV infections in immunocompromised patients [3-6] and have shown that acyclovir has marginal benefit in the acute treatment of herpes labialis in the immunocompetent host [2, 17]. There is still little information, however, on the ability of long-term prophylactic daily acyclovir to suppress recurrent herpes labialis in otherwise healthy persons with frequent recurrences. Attempts to suppress frequently recurrent outbreaks using topical formulations of acyclovir have not been uniformly successful [18, 19]. Oral acyclovir, in dosages of 800 to 1000 mg/d, has shown short-term benefit (≤ 14 days) in the suppression of herpes labialis in patients at high risk for re-activation due to trigeminal ganglion surgery [7], alpine skiing [8], or experimental ultraviolet light exposure [9]. Longer treatment periods have been beneficial in patients with erythema multiforme and in patients with non-genital HSV infection, including some with herpes labialis [20-22].

Our study is the first controlled trial of oral acyclovir for long-term suppression of herpes labialis in otherwise healthy individuals. Treatment with acyclovir, 400 mg twice daily for 4 months, resulted in a 41% reduction in the number of patients experiencing recurrent herpes labialis and a 53% decrease in the number of outbreaks compared with placebo-treated patients. The effect of acyclovir therapy on viral shedding was most notable, with 71% fewer virologically documented recurrences during acyclovir therapy compared with placebo.

Although acyclovir was effective in this study, the observed efficacy was less than that shown in similar trials of suppressive treatment of frequently recurrent genital herpes, where acyclovir therapy over a similar duration resulted in a 74% to 78% reduction in the number of patients having genital outbreaks and 88% reduction in the number of recurrences compared with placebo groups [10-13]. This finding seems surprising in light of the greater in vitro sensitivity of HSV-1 to acyclovir (mean ID₅₀ approximately 0.17 µg/mL), compared with HSV-2 (mean ID₅₀ approximately 0.46 µg/mL), but it is in accord with clinical studies of the acute treatment of herpes labialis, in which oral acyclovir was less effective than it was in the episodic therapy of genital recurrences [17, 23]. The combined observations imply differences in the biological characteristics of recurrent oral and genital herpes that may be important to the potential success of therapy but may not be reflected by the in vitro antiviral sensitivities of the viruses.

Our previous experience with patients who have genital herpes indicated that higher doses of acyclovir seemed necessary to better suppress outbreaks in patients who continued to have outbreaks during treatment [12]. Among patients in the present study who elected to resume open suppressive acyclovir after their first post-treatment recurrence, we noted better results with higher doses (data not shown), but formal assessments of the strategy will need to be done.

Our study included an observation phase during which we could document the actual frequency of disease recurrence before initiating therapy. We noted that only 22 of 56 (39%) patients who entered into the observation phase qualified for treatment by virtue of a sufficient rate of documented recurrences. This contrasts with the experience in genital herpes studies in which the reported frequency of recurrence paralleled quite closely the observed frequency of recurrent disease during the study period [10, 11] and highlights the need to establish conclusively both the diagnosis and the frequency of recurrence in patients with oral herpes before initiating therapy. Patients should be carefully screened to assure that those with aphthous ulcers, cheilitis, or other common recurrent oral and perioral lesions are not mistakenly diagnosed as having recurrent herpes simplex virus infection.

Acyclovir therapy has proved safe for the long-term suppression of recurrent genital herpes infections [12, 13]. Our study establishes the effectiveness of oral acyclovir in suppressing recurrent herpes labialis. The physical and emotional toll of oral herpes is not typically as great as that of genital herpes. Nonetheless, selected patients with documented frequent recurrences may derive benefit from daily oral acyclovir therapy. These patients must be willing to assume the inconvenience, cost, and, in some cases, incomplete efficacy of long-term therapy. For those individuals, daily oral acyclovir therapy may provide a means for managing their disease.